Controlling absence seizures from the cerebellar nuclei via activation of the Gq signaling pathway

Chris de Zeeuw, Jan Claudius Schwitalla*, Johanna Pakusch*, Brix Mucher*, Alexander Bruckner*, Dominic Alexej Depke*, Thomas Fenzl*, Chris de Zeeuw*, Lieke Kros*, Freek Hoebeek*, Melanie D. Mark*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Absence seizures (ASs) are characterized by pathological electrographic oscillations in the cerebral cortex and thalamus, which are called spike-and-wave discharges (SWDs). Subcortical structures, such as the cerebellum, may well contribute to the emergence of ASs, but the cellular and molecular underpinnings remain poorly understood. Here we show that the genetic ablation of P/Q-type calcium channels in cerebellar granule cells (quirky) or Purkinje cells (purky) leads to recurrent SWDs with the purky model showing the more severe phenotype. The quirky mouse model showed irregular action potential firing of their cerebellar nuclei (CN) neurons as well as rhythmic firing during the wave of their SWDs. The purky model also showed irregular CN firing, in addition to a reduced firing rate and rhythmicity during the spike of the SWDs. In both models, the incidence of SWDs could be decreased by increasing CN activity via activation of the G q-coupled designer receptor exclusively activated by designer drugs (DREADDs) or via that of the G q-coupled metabotropic glutamate receptor 1. In contrast, the incidence of SWDs was increased by decreasing CN activity via activation of the inhibitory G i/o-coupled DREADD. Finally, disrupting CN rhythmic firing with a closed-loop channelrhodopsin-2 stimulation protocol confirmed that ongoing SWDs can be ceased by activating CN neurons. Together, our data highlight that P/Q-type calcium channels in cerebellar granule cells and Purkinje cells can be relevant for epileptogenesis, that G q-coupled activation of CN neurons can exert anti-epileptic effects and that precisely timed activation of the CN can be used to stop ongoing SWDs.

Original languageEnglish
Article number197
Number of pages20
JournalCellular and Molecular Life Sciences
Volume79
Issue number4
DOIs
Publication statusPublished - Apr 2022

Bibliographical note

Funding Information:
Open Access funding enabled and organized by Projekt DEAL. JCS was supported by the Ruhr-University Bochum. This work was supported by DFG (German Research Foundation), SFB 1280 (Project number 316803389, Project A21; MDM), MA 5806/2-1 (MDM) and MA 5806/1-2 (MDM) and Netherlands Organization for Scientific Research (NWO-ALW 824.02.001; CIDZ), the Dutch Organization for Medical Sciences (ZonMW 91120067; CIDZ), Medical Neuro-Delta (MD 01092019-31082023; LK, CIDZ), INTENSE LSH-NWO (TTW/00798883; LK, CIDZ), ERC-adv (GA-294775 CIDZ), ERC-POC (nrs. 737619 and 768914; CIDZ), Veni (NWO-ZonMw, 91619109; LK) and Erasmus MC fellowship (LK).

Publisher Copyright:
© 2022, The Author(s).

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